This candidate is an Associate Professor of Gastroenterology and Hepatology at the Medical College of Virginia (MCV). He has played a key role in the growth of the Hepatology program at MCV and has won national recognition for his research on the role of transjugular intrahepatic portasystemic shunts (TIPS) in the treatment of portal hypertension. His career goals are: (1) to be an outstanding clinician, (2) to be a leading scientist in patient- oriented research in liver disease, and (3) to train junior clinicians as bio-medical scientists. This application has been written to mainly consolidate his status as a clinical scientist and teacher. During the period of the proposed studies, the candidate will perform research and serve as a mentor to junior colleagues. Two specific research projects will be performed: (1) a randomized prospective multi-center trial of total paracenteses (TP) vs TP + TIPS for refractory ascites of which he is the principal investigator. (2): studies on the pathogenesis of nonalcoholic steatohepatitis (NASH), a common yet poorly understood disease. It is hypothesized that susceptibility to NASH results from spontaneous mutations of mitochondrial DNA (mtDNA) which cause defective expression of electron-transport chain enzymes in a fraction of hepatocyte mitochondria. Functionally, this results in abnormal oxidation/phosphorylation. when such individuals develop insulin-resistance e.g. from obesity or diabetes, increased lipolysis provides more fatty acid for hepatic uptake and beta oxidation. The resultant oxidative stress in hepatocytes with abnormal mitochondria generates free radicals which cause lipid peroxidation and cell injury. This will be tested by (1) comparison of insulin sensitivity and lipolysis in patients with NASH to three control groups( non-alcoholic fatty liver, matched normal controls, and non-fatty liver disease) using an euglycemic clamp, (2) comparison of hepatocyte mitochondrial structure and function across these four groups by electron microscopy and histochemical assessment of cytochrome oxidase and succinate dehydrogenase, (3) comparison of lipid peroxides in liver biopsy homogenates across these four groups, and (4) comparison of the prevalence and types of mtDNA mutations across these four groups. The latter studies will be done by Dr. Vantuyle (Dept. Biochem, MCV). The institutional and departmental environment as well as the facilities and resources are excellent for career development in academic medicine.